Work from our laboratory demonstrates that cytochrome P450s metabolize arachidonic acid to epoxy-eicosatrienoic acids (EETs). These eicosanoids affect vascular tone, modulate fluid/electrolyte transport and are involved in Ca++ signaling. Current research involves: (1) characterization of CYP2J subfamily P450s at the biochemical/molecular levels; (2) studies on the regulation of CYP2J expression; (3) evaluation of the functional roles of CYP2J products in cell/organ physiology; and (4) examination of this pathway in animal models of disease (including ischemic heart disease, hypertension and atherosclerosis). We have cloned the mouse Cyp2j5 gene, expressed the corresponding cDNA and shown that the recombinant enzyme catalyzes the biosynthesis of EETs. Unlike human CYP2J2, mouse CYP2J5 has a narrow tissue distribution and appears to be one of the major renal P450s. Within the kidney, CYP2J5 is localized to proximal tubules and collecting ducts, sites where EETs modulate salt/water transport, and mediate the effects of angiotensin II and arginine vasopressin. Renal CYP2J5 expression is up-regulated by androgens and these effects are mediated by the androgen receptor. Renal CYP2J5 expression is also down-regulated by estrogens and female ERKO mice express abundant CYP2J5 protein. CYP2J5 is developmentally regulated in the kidney and maximal levels occur during a critical period of postnatal renal development when the pressure-natruresis relationship is established and when renal functional abnormalities are first demonstrable in animals who develop hypertension. CYP2J-specific antibodies immunoreact with a 55kDa kidney protein that is expressed at higher levels in spontaneously hypertensive rats than in normotensive controls. Hypertensive animals also exhibit markedly increased renal epoxygenase activity. These findings suggest a possible role for CYP2J gene products in the development and/or maintenance of the hypertension. Efforts are currently underway to: (a) construct mice in which the Cyp2j5 gene has been disrupted in order to study the functional significance of this P450 in kidney development, renal physiology and blood pressure regulation; (b) identify the 55kDa CYP2J immunoreactive protein which is overexpressed in hypertensive animals; and (c) analyze the Cyp2j5 promoter to elucidate the molecular mechanisms involved in its tissue-specific expression, regulation by sex hormones and developmental regulation. - arachidonic acid cytochrome P450 epoxyeicosatrienoic acid eicosanoids hypertension renal physiology - Human Subjects